PROJECT SUMMARY/ABSTRACT The long-term goal of these experiments is to define the organization of the neural networks responsible for anorexiainrats.Inparticular,studieswillfocusoninteractionsbetweenthetelencephalon,andthehypothalamus and hindbrain, since the telencephalon likely plays a critical role in clinically-relevant anorexias. To generate anorexia experimentally, the project will use the chronic dehydration that follows drinking hypertonic saline. This well-documented model has the advantage that its development and intensity can be simply and reliably controlled. Furthermore, the anorexia is quickly reversed when the animal drinks water. The main hypothesis is that the lateral hypothalamic area and the paraventricular nucleus of the hypothalamus contain neurons that constitute a feeding behavior controller, and are sites where distinct feeding stimuli converge to control the core circuits that drive feeding. The goal is to determine the locations of the points of convergence, and to explore how these are affected during anorexia. Three hypotheses will be addressed by the specific aims. They are: 1) Information encoding nucleus accumbens shell (ACBsh)-muscimol and 2-deoxy-D-glucose- driven feeding converges onto the same neurons in the LHA and PVH; 2) ACBsh-muscimol feeding requires input from either the hindbrain or NPY-Y1 receptor expressing neurons in the mediobasal hypothalamus (MBH) for full expression; 3) projections from either the hindbrain or NPY-Y1 receptor expressing neurons in the MBH to the PVH and LHA are required for water-back feeding. Experiments will use two approaches: first, a fine-grained analysis of the structure of ACBsh-muscimol and 2-deoxy-D-glucose-driven feeding in control and anorexic animals; second, a novel immunocytochemical coincidence detection (based on the differential accumulation and degradation rates of Fos and phosphorylated-ERK/2) that reveals neurons that are activated by two convergent feeding stimuli. Circuits will be manipulated using saporin-based immunotoxic lesions that destroy either the ascending catecholaminergic neurons from the hindbrain, or NPY-Y1 receptor expressing neurons in the MBH. Importantly, the types of feeding that are impacted these two techniques are clearly dissociable. Collectively, the experiments in this project are designed to make major contributions towards elucidating the organization and function of the neural circuits responsible for anorexia in animals in a way that will ultimately help to clarify the neural substrates of clinically important anorexias. PROJECT NARRATIVE Eating disorders, and anorexia nervosa in particular, are significant clinical problems that have poor outcomes; indeed, anorexia nervosa is one of the deadliest of all psychiatric disorders. Treatment of eating disorders is notoriously difficult, with pharmacological intervention being frustratingly ineffective. The proposed studies aim to delineate the neural circuitry responsible for generating an experimentally-tractable type of anorexia in animals, with a view to developing neural network models that can be applied to clinically-relevant anorexias.